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1.
PLoS Med ; 17(9): e1003307, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32931494

RESUMO

BACKGROUND: Hypertension, together with obesity, is a leading cause of mortality and disability. Whilst metabolic surgery offers remission of several metabolic comorbidities, the effect for patients with hypertension remains controversial. The objective of the present study was to evaluate the effect of metabolic surgery on cardiovascular events and mortality on patients with morbid obesity (body mass index [BMI] ≥ 35 kg/m2) and hypertension. METHODS AND FINDINGS: We conducted a matched cohort study of 11,863 patients with morbid obesity and pharmacologically treated hypertension operated on with metabolic surgery and a matched non-operated-on control group of 26,199 subjects with hypertension (matched by age, sex, and area of residence) of varied matching ratios from 1:1 to 1:9, using data from the Scandinavian Obesity Surgery Register (SOReg), the Swedish National Patient Registers (NPR) for in-hospital and outpatient care, the Swedish Prescribed Drug Register, and Statistics Sweden. The main outcome was major adverse cardiovascular event (MACE), defined as first occurrence of acute coronary syndrome (ACS) event, cerebrovascular event, fatal cardiovascular event, or unattended sudden cardiac death. The mean age in the study group was 52.1 ± 7.46 years, with 65.8% being women (n = 7,810), and mean BMI was 41.9 ± 5.43 kg/m2. MACEs occurred in 379 operated-on patients (3.2%) and 1,125 subjects in the control group (4.5%). After adjustment for duration of hypertension, comorbidities, and education, a reduction in risk was seen in the metabolic surgery group (adjusted hazard ratio [HR] 0.73, 95% confidence intervals [CIs] 0.64-0.84, P < 0.001). The surgery group had lower risk for ACS events (adjusted HR 0.52, 95% CI 0.41-0.66, P < 0.001) and a tendency towards lower risk for cerebrovascular events (adjusted HR 0.81, 95% CI 0.63-1.01, P = 0.060) compared with controls. The main limitations with the study were the lack of information on BMI and history of smoking in the control group and the nonrandomised study design. CONCLUSION: Metabolic surgery on patients with morbid obesity and pharmacologically treated hypertension was associated with lower risk for MACEs and all-cause mortality compared with age- and sex-matched controls with hypertension from the general population.


Assuntos
Cirurgia Bariátrica/efeitos adversos , Hipertensão/metabolismo , Obesidade Mórbida/cirurgia , Adulto , Cirurgia Bariátrica/tendências , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Hipertensão/cirurgia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/cirurgia , Obesidade Mórbida/complicações , Obesidade Mórbida/mortalidade , Modelos de Riscos Proporcionais , Fatores de Risco , Suécia/epidemiologia
2.
Nat Commun ; 11(1): 4798, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968066

RESUMO

Myeloid cells are known mediators of hypertension, but their role in initiating renin-induced hypertension has not been studied. Vitamin D deficiency causes pro-inflammatory macrophage infiltration in metabolic tissues and is linked to renin-mediated hypertension. We tested the hypothesis that impaired vitamin D signaling in macrophages causes hypertension using conditional knockout of the myeloid vitamin D receptor in mice (KODMAC). These mice develop renin-dependent hypertension due to macrophage infiltration of the vasculature and direct activation of renal juxtaglomerular (JG) cell renin production. Induction of endoplasmic reticulum stress in knockout macrophages increases miR-106b-5p secretion, which stimulates JG cell renin production via repression of transcription factors E2f1 and Pde3b. Moreover, in wild-type recipient mice of KODMAC/miR106b-/- bone marrow, knockout of miR-106b-5p prevents the hypertension and JG cell renin production induced by KODMAC macrophages, suggesting myeloid-specific, miR-106b-5p-dependent effects. These findings confirm macrophage miR-106b-5p secretion from impaired vitamin D receptor signaling causes inflammation-induced hypertension.


Assuntos
Hipertensão Renal/metabolismo , Hipertensão/metabolismo , Macrófagos/metabolismo , MicroRNAs/metabolismo , Nefrite/metabolismo , Renina/metabolismo , Animais , Medula Óssea , Transplante de Medula Óssea , Modelos Animais de Doenças , Fator de Transcrição E2F1/metabolismo , Estresse do Retículo Endoplasmático , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides , Receptores de Calcitriol , Vitamina D
3.
Am J Physiol Heart Circ Physiol ; 319(4): H793-H796, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32886002

RESUMO

The 60-kDa heat shock protein (HSP60) is a chaperone essential for mitochondrial proteostasis ensuring thus sufficient aerobic energy production. In pathological conditions, HSP60 can be translocated from the mitochondria and excreted from the cell. In turn, the extracellular HSP60 has a strong ability to trigger and enhance inflammatory response with marked proinflammatory cytokine induction, which is mainly mediated by Toll-like receptor binding. Previous studies have found increased circulating levels of HSP60 in hypertensive patients, as well as enhanced HSP60 expression and membrane translocation in the hypertrophic myocardium. These observations are of particular interest, since they could provide a possible pathophysiological explanation of the severe course and worse outcome of severe acute respiratory syndrome coronavirus 2 infection in hypertensive patients, repeatedly reported during the recent coronavirus disease 2019 (COVID-19) pandemic and related to hyperinflammatory response and cytokine storm development during the third phase of the disease. In this regard, pharmacological inhibition of HSP60 could attract attention to potentially ameliorate inappropriate inflammatory reaction in severe COVID-19 patients. Among HSP60 antagonizing drugs, mizoribine is the most intriguing, since it is clinically approved and exerts antiviral activity. However, this topic requires to be further scrutinized.


Assuntos
Betacoronavirus/patogenicidade , Chaperonina 60/metabolismo , Infecções por Coronavirus/metabolismo , Hipertensão/metabolismo , Mediadores da Inflamação/metabolismo , Pneumonia Viral/metabolismo , Animais , Chaperonina 60/antagonistas & inibidores , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Imunossupressores/uso terapêutico , Mediadores da Inflamação/antagonistas & inibidores , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Prognóstico , Ribonucleosídeos/uso terapêutico , Transdução de Sinais
4.
Life Sci ; 258: 118156, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735886

RESUMO

AIMS: Flavin adenine dinucleotide (FAD), participates in fatty acid ß oxidation as a cofactor, which has been confirmed to enhance SCAD activity and expression. However, the role of FAD on hypertensive vascular remodeling is unclear. In this study, we investigated the underlying mechanisms of FAD on vascular remodeling and endothelial homeostasis. MAIN METHODS: Morphological examination of vascular remodeling were analyzed with hematoxylin and eosin (HE) staining, Verhoeff's Van Gieson (EVG) staing, Dihydroethidium (DHE) staining and Sirius red staining. HUVECs apoptotic rate was detected by flow cytometry and HUVECs reactive oxygen species (ROS) was detected by DHE-probe. Enzymatic reactions were used to detect SCAD enzyme activity. The protein level was detected by Western Blots, the mRNA level was detected by quantitative real-time PCR. KEY FINDINGS: In vivo experiments, FAD significantly decreased blood pressure and ameliorated vascular remodeling by increasing SCAD expression, Nitric Oxide (NO) production and reducing ROS production. In vitro experiments, FAD protected against the tBHP induced injury in HUVEC, by increasing the activity of SCAD, increasing the elimination of free fatty acid (FFA), scavenging ROS, reducing apoptotic rate, thereby improving endothelial cell function. SIGNIFICANCE: FAD has a new possibility for preventing and treating hypertensive vascular remodeling.


Assuntos
Acil-CoA Desidrogenases/metabolismo , Ativadores de Enzimas/uso terapêutico , Flavina-Adenina Dinucleotídeo/uso terapêutico , Hipertensão/tratamento farmacológico , Remodelação Vascular/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Flavina-Adenina Dinucleotídeo/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Ratos Endogâmicos SHR , Ratos Wistar
5.
Nat Commun ; 11(1): 4222, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839436

RESUMO

Our understanding of Na+ homeostasis has recently been reshaped by the notion of skin as a depot for Na+ accumulation in multiple cardiovascular diseases and risk factors. The proposed water-independent nature of tissue Na+ could induce local pathogenic changes, but lacks firm demonstration. Here, we show that tissue Na+ excess upon high Na+ intake is a systemic, rather than skin-specific, phenomenon reflecting architectural changes, i.e. a shift in the extracellular-to-intracellular compartments, due to a reduction of the intracellular or accumulation of water-paralleled Na+ in the extracellular space. We also demonstrate that this accumulation is unlikely to justify the observed development of experimental hypertension if it were water-independent. Finally, we show that this isotonic skin Na+ excess, reflecting subclinical oedema, occurs in hypertensive patients and in association with aging. The implications of our findings, questioning previous assumptions but also reinforcing the importance of tissue Na+ excess, are both mechanistic and clinical.


Assuntos
Edema/metabolismo , Homeostase/fisiologia , Sódio/metabolismo , Equilíbrio Hidroeletrolítico/fisiologia , Envelhecimento/metabolismo , Animais , Edema/diagnóstico , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Miocárdio/metabolismo , Especificidade de Órgãos , Concentração Osmolar , Potássio/metabolismo , Ratos Endogâmicos WKY , Pele/metabolismo , Fatores de Transcrição/metabolismo
6.
PLoS One ; 15(8): e0238114, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822432

RESUMO

INTRODUCTION: Hypertension among HIV positive patients in low- and middle-income countries has got little attention and data on the problem is limited in Ethiopia. Hence, this study aims to determine the magnitude of hypertension and its associated factors among HIV-positive patients receiving care at referral hospitals of Northwest Ethiopia. MATERIALS AND METHODS: A cross-sectional study design was conducted to determine the burden of hypertension in patients living with HIV receiving care at referral hospitals of Northwest Ethiopia between November 2018 and May 2019. Four hundred seven randomly selected adult patients were included for the study. Using standardized questionnaire, sociodemographic, behavioral and clinical data were collected. Anthropometric parameters, fasting blood sugar as well as lipid profiles were determined. Bivariate and multivariate binary logistic regression analysis was performed. RESULT: A total of 407 study subjects with 98% response rate have been included in this study. The prevalence of hypertension was 14.0% (95% CI: 10.63,17.37). Elementary educational status as compared to no education [AOR (95% CI) 2.75 (1.12,6.75), p< 0.05], moderate monthly income compared to low [AOR (95% CI) 4.27 (2.09,8.73), p<0.01], waist circumference [AOR (95% CI) 4.27 (2.09,8.73), p<0.01], taking concomitant other drug therapy [AOR (95% CI) 5.72 (2.25,14.54), p<0.01] and duration of antiretroviral therapy [AOR (95% CI) 1.12 (1.04,1.20) were significantly associated with hypertension. CONCLUSION: Hypertension is not uncommon in patients living with HIV. Educational status, monthly income, waist circumference, concomitant drug therapy and duration of antiretroviral therapy are linked with hypertension. The finding pinpoints that health care providers should work up on risk factors to reduce the burden of hypertension among the patients.


Assuntos
Infecções por HIV/complicações , Hipertensão/epidemiologia , Adulto , Estudos Transversais , Etiópia/epidemiologia , Feminino , HIV-1/metabolismo , HIV-1/patogenicidade , Humanos , Hipertensão/metabolismo , Modelos Logísticos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Prevalência , Encaminhamento e Consulta
7.
Chemosphere ; 255: 126984, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32679627

RESUMO

Experimental and epidemiological studies have suggested an association between exposure to polychlorinated biphenyls (PCBs), ubiquitous environmental toxic compounds, and the risk of hypertension. We conducted a systematic review and meta-analysis of epidemiological studies of the association between PCB exposure and the risk of hypertension. Studies were identified by searching PubMed, Embase and Web of Science and by reviewing reference lists. Study-specific risk estimates comparing the highest versus lowest quantile of PCB distribution were combined using random-effects models. We identified 10 cross-sectional studies, 6 cohort studies, and 1 nested case-control study. A pooled excess risk of hypertension was found for total PCBs (OR 1.70, 95% CI 1.28-2.26), dioxin-like (DL)-PCBs (OR 1.46, 1.19-1.79), but not for non-dioxin like (NDL)-PCBs (OR 1.19, 0.81-1.73) comparing the highest with the lowest quartile of the distribution. According to a dose-response meta-analysis, a linear dose-effect relationship was found for total PCBs [OR 2.23 (95% CI: 1.59-3.14) for 1000 ng PCB/g lipid increase]. This positive association remained when stratifying the analyses by study design (cohort vs cross-sectional studies) and population (general population vs high exposed workers/residents). Among single PCB congeners, DL-PCB 105 and 118, and non-DL-PCB138 and 153 were related to hypertension. In conclusion, this meta-analysis suggests that exposure to PCBs, particularly to DL-PCBs, may be a risk factor for hypertension, independently of other risk factors.


Assuntos
Exposição Ambiental/estatística & dados numéricos , Hipertensão/epidemiologia , Bifenilos Policlorados/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Dioxinas , Feminino , Humanos , Hipertensão/metabolismo , Pessoa de Meia-Idade , Bifenilos Policlorados/análise , Dibenzodioxinas Policloradas , Fatores de Risco
8.
Proc Natl Acad Sci U S A ; 117(29): 17369-17380, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32641503

RESUMO

Voltage-gated L-type Ca2+ channel (Cav1.2) blockers (LCCBs) are major drugs for treating hypertension, the preeminent risk factor for heart failure. Vascular smooth muscle cell (VSMC) remodeling is a pathological hallmark of chronic hypertension. VSMC remodeling is characterized by molecular rewiring of the cellular Ca2+ signaling machinery, including down-regulation of Cav1.2 channels and up-regulation of the endoplasmic reticulum (ER) stromal-interacting molecule (STIM) Ca2+ sensor proteins and the plasma membrane ORAI Ca2+ channels. STIM/ORAI proteins mediate store-operated Ca2+ entry (SOCE) and drive fibro-proliferative gene programs during cardiovascular remodeling. SOCE is activated by agonists that induce depletion of ER Ca2+, causing STIM to activate ORAI. Here, we show that the three major classes of LCCBs activate STIM/ORAI-mediated Ca2+ entry in VSMCs. LCCBs act on the STIM N terminus to cause STIM relocalization to junctions and subsequent ORAI activation in a Cav1.2-independent and store depletion-independent manner. LCCB-induced promotion of VSMC remodeling requires STIM1, which is up-regulated in VSMCs from hypertensive rats. Epidemiology showed that LCCBs are more associated with heart failure than other antihypertensive drugs in patients. Our findings unravel a mechanism of LCCBs action on Ca2+ signaling and demonstrate that LCCBs promote vascular remodeling through STIM-mediated activation of ORAI. Our data indicate caution against the use of LCCBs in elderly patients or patients with advanced hypertension and/or onset of cardiovascular remodeling, where levels of STIM and ORAI are elevated.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Hipertensão/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Molécula 2 de Interação Estromal/metabolismo , Moléculas de Interação Estromal/metabolismo , Remodelação Vascular/fisiologia , Animais , Anti-Hipertensivos/farmacologia , Cálcio/metabolismo , Canais de Cálcio Tipo L/efeitos dos fármacos , Membrana Celular/metabolismo , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Técnicas de Inativação de Genes , Células HEK293 , Insuficiência Cardíaca , Humanos , Proteínas de Membrana/genética , Miócitos de Músculo Liso , Proteínas de Neoplasias , Proteína ORAI1/genética , Ratos , Molécula 1 de Interação Estromal/genética , Molécula 2 de Interação Estromal/genética
9.
PLoS One ; 15(7): e0236451, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697789

RESUMO

BACKGROUND: Lifestyle habits associate with metabolic health in overall populations. Whether such association is similar among subjects with a different nutritional status has been less studied. We aimed to (i) determine the prevalence of metabolic phenotypes in Chile, and (ii) determine the association between lifestyle habits and metabolic health according to the nutritional status. METHODS: The National Health Survey of Chile 2016-2017 was analyzed. A metabolically unhealthy phenotype was defined as manifesting ≥3 of the following risk factors: elevated blood pressure, elevated triglycerides, elevated glucose, elevated waist circumference, or reduced high-density lipoprotein cholesterol. Individuals manifesting <2 risk factors were considered as healthy. The nutritional status was defined as normal weight (18.5 to <25 kg/m2), overweight (25 to <30 kg/m2) or obesity (≥30 kg/m2). Questionnaires were used to estimate smoking habits, alcohol intake, sedentary behavior, moderate-vigorous physical activity, fruits/vegetables consumption, and fish/seafood consumption. The association (odds ratio [95%CI]) between lifestyle habits and metabolic health was determined within each nutritional status, adjusting for age, sex, BMI (in kg/m2), and education. RESULTS: The prevalence of a metabolically unhealthy phenotype was 36% in the overall sample. Such a prevalence was 7%, 33% and 58% among subjects with normal weight, overweight and obesity, respectively. In subjects with normal weight, the highest quartile of fruits/vegetables consumption was associated with reduced odds of having a metabolically unhealthy phenotype (0.09 [0.01-0.48]). In subjects with obesity, the highest quartile of moderate-vigorous physical activity was associated with reduced odds of having a metabolically unhealthy phenotype (0.29 [0.09-0.91]). CONCLUSION: One third of the Chilean population manifests an unhealthy phenotype. We identified associations between lifestyle habits and metabolic health that are specific to the nutritional status. Thus, emphasizing fruits/vegetables consumption in subjects with normal weight, and physical activity in subjects with obesity, may maximize the benefits of public health interventions.


Assuntos
Hábitos , Estilo de Vida , Síndrome Metabólica/epidemiologia , Estado Nutricional/fisiologia , Adolescente , Adulto , Idoso , Glicemia/análise , Chile/epidemiologia , HDL-Colesterol/sangue , Estudos Transversais , Escolaridade , Feminino , Inquéritos Epidemiológicos/estatística & dados numéricos , Humanos , Hipertensão/sangue , Hipertensão/epidemiologia , Hipertensão/metabolismo , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade/metabolismo , Sobrepeso/sangue , Sobrepeso/epidemiologia , Sobrepeso/metabolismo , Prevalência , Fatores de Risco , Circunferência da Cintura/fisiologia , Adulto Jovem
10.
Life Sci ; 258: 118124, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32702443

RESUMO

AIMS: Ketogenic diet (KD) has been proposed to be an effective lifestyle intervention for metabolic syndrome. However, the effects of KD on hypertension have not been well investigated. The present study aimed to investigate the effects and underling mechanisms of KD on hypertension in spontaneously hypertensive rats (SHRs). MATERIALS AND METHODS: SHRs were subjected to normal diet or KD for 4 weeks, starting at the age of 10 weeks. Then, the blood pressure and vascular function were assessed. Next, the eNOS expression, inflammatory factors and relative signaling pathway were examined. Human umbilical vein endothelial cells were used to investigate the underlying mechanism account for the effect of ketone on inflammation and eNOS expression. KEY FINDINGS: Compared with the normal diet, KD was indicated to aggravate hypertension and impaire endothelium-dependent relaxation in mesenteric arteries of SHRs. eNOS and CD31 expression in mesenteric arteries were also significantly suppressed by KD. In addition, KD markedly increased the activation of NF-κB pathway and the expression of IL1-ß and TNF-α. In vitro, results showed that inhibition of NF-κB could rescue the adverse effects of ketone body and TGF-ß on eNOS expression and inflammation response. SIGNIFICANCE: Our study indicated that KD impaired endothelium-dependent relaxation in mesenteric arteries and aggravated the development of hypertension in SHRs, suggesting that it should be more cautious to apply KD into clinical application in hypertensive individuals.


Assuntos
Dieta Cetogênica , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Hipertensão/metabolismo , Hipertensão/patologia , NF-kappa B/metabolismo , Animais , Biomarcadores/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Corpos Cetônicos/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/patologia , Óxido Nítrico Sintase Tipo III/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos Endogâmicos SHR , Vasodilatação , Perda de Peso
11.
Diabetes Res Clin Pract ; 167: 108349, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32712124

RESUMO

AIM: While there are rampant deaths reported worldwide due to novel corona virus (COVID-19) on one side, hypertension, diabetes and renal failure are emerging comorbidities with mortality risk due to respiratory failure on the other side. The link of these morbidities with renin angiotensin system (RAS) and angiotensin converting enzyme-2 (ACE2) as the site of the multiplication of COVID-19 has widely been accepted. The objective of this research report was to delineate the clinical characteristics with COVID-19 infection with RAS and to consider its significance not just for the search of novel antiviral drugs, but for the management and prevention of death of patients with COVID-19. METHODS: It was a retrospective case series analysis of demographic and clinical data with associated comorbidities of 206 deaths reported in India up to 10th April 2020. The data were available from the official release from Ministry of Health and Family welfare, Government of India. This was followed by a literature search to correlate the available evidence for their possible relationship with RAS. RESULTS: The demographic data were consistent with those reported from other countries. The death (53.4%) was more common in patients with age above 60 years and men (69.3%) were more susceptible as compared to women (30.68%).We found that 50.5% of the deceased patients had pre-existing comorbidities. Diabetes and hypertension were the major comorbidities in 27.8% and 22.1% of the deceased cases respectively. Although respiratory and cardiac problems were prevalent at the time of death, the pre-existing pulmonary disease was comparatively less prevalent. Only 13.6% of the deceased were having pre-existing respiratory problems and 6.2% had cardiac ailments. We could correlate the reports that RAS plays a significant role in the prognosis of the disease. CONCLUSIONS: Patients with cardiovascular diseases, diabetes mellitus and hypertension are at greater risk for developing COVID-19 infection. There may be massive derangement of the entire RAS after the attack of COVID-19 and hence, patients with these pre-existing comorbidities and on ACE inhibitors or angiotensin receptor blockers should be monitored carefully considering the role of RAS in the prognosis of COVID-19 infections.


Assuntos
Infecções por Coronavirus/mortalidade , Diabetes Mellitus/epidemiologia , Hipertensão/epidemiologia , Pneumonia Viral/mortalidade , Sistema Renina-Angiotensina , Adulto , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Betacoronavirus , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/metabolismo , Comorbidade , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/metabolismo , Feminino , Cardiopatias/tratamento farmacológico , Cardiopatias/epidemiologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral/metabolismo , Doenças Respiratórias/epidemiologia , Estudos Retrospectivos
12.
Arterioscler Thromb Vasc Biol ; 40(9): 2108-2113, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640904

RESUMO

OBJECTIVE: Renin cleavage of angiotensinogen has species specificity. As the residues at positions 11 and 12 are different between human angiotensinogen and mouse angiotensinogen, we determined whether these 2 residues in angiotensinogen affect renin cleavage and angiotensin II-mediated blood pressure regulation and atherosclerosis using an adenoassociated viral approach for manipulating angiotensinogen in vivo. Approach and Results: Hepatocyte-specific angiotensinogen deficient (hepAGT-/-) mice in an LDL receptor-deficient background were infected with adenoassociated virals containing a null insert, human angiotensinogen, or mouse angiotensinogen expressing the same residues of the human protein at positions 11 and 12 (mouse angiotensinogen [L11V;Y12I]). Expression of human angiotensinogen in hepAGT-/- mice led to high plasma human angiotensinogen concentrations without changes in plasma endogenous mouse angiotensinogen, plasma renin concentrations, blood pressure, or atherosclerosis. This is consistent with human angiotensinogen not being cleaved by mouse renin. To determine whether the residues at positions 11 and 12 in human angiotensinogen lead to the inability of mouse renin to cleave human angiotensinogen, hepAGT-/- mice were injected with adenoassociated viral vector encoding mouse angiotensinogen (L11V;Y12I). Expression of mouse angiotensinogen (L11V;Y12I) in hepAGT-/- mice resulted in increased plasma mouse angiotensinogen concentrations, reduced renin concentrations, and increased renal AngII concentrations that were comparable to their concentrations in hepAGT+/+ mice. This mouse angiotensinogen variant increased blood pressure and atherosclerosis in hepAGT-/- mice to the magnitude of hepAGT+/+ mice. CONCLUSIONS: Replacement of L11 and Y12 to V11 and I12, respectively, in mouse angiotensinogen does not affect renin cleavage, blood pressure, and atherosclerosis in LDL receptor-deficient mice.


Assuntos
Angiotensina II/metabolismo , Angiotensinogênio/metabolismo , Aterosclerose/metabolismo , Pressão Sanguínea , Hepatócitos/metabolismo , Hipertensão/metabolismo , Renina/metabolismo , Substituição de Aminoácidos , Angiotensinogênio/deficiência , Angiotensinogênio/genética , Animais , Aterosclerose/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Camundongos Knockout , Placa Aterosclerótica , Receptores de LDL/genética , Receptores de LDL/metabolismo , Especificidade da Espécie
13.
Chem Biol Interact ; 326: 109145, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32485150

RESUMO

The renin-angiotensin-aldosterone system (RAAS) is a hormonal system that has a critical role in maintaining the normotensive state and electrolyte balance of the organism. The RAAS also has an important influence in the development of various pathophysiological conditions especially those concerning the renal system, cardiovascular system and hypertension. One of the consequences of the RAAS system is an increase in the generation of the reactive oxygen species (ROS) that causes an increase in oxidative stress, which may play a role in the development or exacerbation of such pathological conditions. Blocking this system at multiple points has been advantageous in the clinical management of these disorders. The key blockers that had gained predominant clinical use for such manifestations were angiotensin receptor blockers and angiotensin-converting enzyme (ACE) inhibitors. However, their prolonged use caused a compensatory increase in renin and angiotensin I levels. The blocking of the system at the initial stages by blocking renin was of advantage to overcome such compensation. Such a renin blocker that gained widespread use was aliskiren. It is the first oral renin inhibitor that was approved for use in 2007. Although the opinions are varied about the use and future of renin inhibitors as antihypertensive agents, aliskiren has been well documented to have antioxidant effects. Aliskiren functions as an antioxidant by lowering the increase in ROS that are produced by the RAAS system at doses independent of decreasing the blood pressure. In the present review we discuss the antioxidant properties of aliskiren independent of its blood pressure lowering property.


Assuntos
Amidas/farmacologia , Amidas/uso terapêutico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Fumaratos/farmacologia , Fumaratos/uso terapêutico , Hipertensão/tratamento farmacológico , Animais , Pressão Sanguínea/efeitos dos fármacos , Humanos , Hipertensão/metabolismo , Espécies Reativas de Oxigênio/metabolismo
14.
Medicine (Baltimore) ; 99(24): e20674, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541513

RESUMO

BACKGROUND: Previous studies have shown inconsistent outcomes in the efficacy of angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) on insulin resistance (IR). Hence, we aim to compare the efficacy of ACE inhibitors with ARBs on IR in hypertensive patients. METHODS: Five electronic databases (included The Cochrane Library, MEDLINE, Embase, Web of Science, and Cochrane Central Register of Controlled Trials) will be searched. Randomized controlled trials (RCTs) will be included if they recruited hypertensive participants for assessing the effect of ACE inhibitors on IR versus ARBs. The primary outcome will be IR (using recognized methods such as homeostasis model assessment of insulin resistance), secondary outcomes will be blood pressure, fasting plasma glucose, fasting plasma insulin. Relevant literature search, data extraction, and quality assessment will be performed by 2 researchers independently, and the third researcher will be involved in a discussion for any disagreements. All analyses will be performed based on the Cochrane Handbook for Systematic Reviews of Interventions. Stata 12.0 software will be used for statistical analysis. The effect size of dichotomous data will be measured using the odds ratio (OR), and the effect size of continuous data will be measured using the standardized mean difference. And 95% confidence intervals will be calculated. Heterogeneity will be tested by χ-based Cochran Q statistic and I statistic. Sensitivity analysis and subgroup analysis will be used to observe changes in the pooled effect size and heterogeneity between included studies, to assess the reliability and stability of the pooled results. The funnel plot and Egger's and Begg's tests will be used to judge publication bias, and the trim and fill method will be used to correct the funnel asymmetry caused by publication bias. P < 0.05 will be considered to indicate a statistically significant result. RESULTS: This systematic review and meta-analysis will assess the efficacy of ACE inhibitors versus ARBs on IR in hypertensive patients. CONCLUSIONS: Our study will show the efficacy of ACE inhibitors versus ARBs on IR in hypertensive patients. And it may find a more beneficial therapeutic option to assist clinicians in making clinical decisions. ETHICS AND DISSEMINATION: This study is a protocol for systematic review and meta-analysis of the efficacy of ACE inhibitors and ARBs on IR in hypertensive patients. This systematic review and meta-analysis will be published in a journal and disseminated in print by peer-review. INPLASY REGISTRATION NUMBER: INPLASY202050032.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hipertensão/metabolismo , Resistência à Insulina , Metanálise como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Clin Exp Hypertens ; 42(8): 748-752, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-32564622

RESUMO

OBJECTIVE: This study aimed to explore the mechanism of hypertensive brain damage from ferroptosis pathway. METHODS: Ten 22-week-old SHR rats were labeled as hypertension group(HBP), while ten WKY rats of comparable age, weight were used as normal blood pressure group(NBP). After 2 weeks of feeding, hypertensive brain damage was observed by comparing the pathological changes of brain tissue in SHR rats and WKY rats. Furthermore, the expression of GPX4 in the cerebral cortex was detected by immunofluorescence. The content of GSH was determined by spectrophotometer. The content of iron was detected by ferrous chromite colorimetry. And the content of MDA was determined by spectrophotometer. Compare the difference to investigate the role of ferroptosis mechanism in hypertensive brain damage. RESULTS: Brain damage occurred in 24-week-old SHR rats compared with WKY rats. In the HBP, the GPX4 and GSH were significantly lower than those in the NBP, and the total iron content and MDA were significantly increased. CONCLUSION: Thses findings suggest ferroptosis is closely related to hypertensive brain damage. Elevated blood pressure leads to iron overload in the brain. Excessive iron increases oxidative stress and lipid peroxidation in the brain, and eventually causes brain damage.


Assuntos
Encéfalo/patologia , Ferroptose , Hipertensão/patologia , Animais , Pressão Sanguínea , Encéfalo/metabolismo , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Peroxidação de Lipídeos , Masculino , Estresse Oxidativo/fisiologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
16.
Hypertension ; 76(2): 478-487, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32564694

RESUMO

We showed ACE (angiotensin-converting enzyme) 2 is higher in the kidney of male compared with female mice. To further investigate this sex difference, we examined the role of ACE2 in Ang-[1-8] (angiotensin [1-8])-induced hypertension and regulation of the renin-angiotensin system in the kidney of WT (wild type) and Ace2 KO (knockout) mice. Mean arterial pressure rose faster in WT male than WT female mice after Ang-[1-8] infusion. This sex difference was attenuated in ACE2 KO mice. Ang-[1-8] infusion reduced glomerular AT1R (angiotensin type 1 receptor) binding in WT female mice by 30%, and deletion of Ace2 abolished this effect. In contrast, Ang-[1-8] infusion increased glomerular AT1R binding in WT male mice by 1.2-fold, and this effect of Ang-[1-8] persisted in Ace2 KO male mice (1.3-fold). ACE2 also had an effect on renal protein expression of the neutral endopeptidase NEP (neprilysin), the enzyme that catabolizes Ang-[1-10] (angiotensin [1-10]), the precursor of Ang-[1-8]. Ang-[1-8] infusion downregulated NEP protein expression by 20% in WT male, whereas there was a slight increase in NEP expression in WT female mice. Deletion of Ace2 resulted in lowered NEP expression after Ang-[1-8] infusion in both sexes. These findings suggest sex-specific ACE2 regulation of the renin-angiotensin system contributes to female protection from Ang-[1-8]-induced hypertension. These findings have ramifications for the current coronavirus disease 2019 (COVID-19) pandemic, especially in hypertension since ACE2 is the SARS-CoV-2 receptor and hypertension is a major risk factor for poor outcomes.


Assuntos
Betacoronavirus , Pressão Sanguínea/fisiologia , Infecções por Coronavirus/complicações , Hipertensão/fisiopatologia , Peptidil Dipeptidase A/biossíntese , Pneumonia Viral/complicações , Sistema Renina-Angiotensina/fisiologia , Animais , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/fisiopatologia , Feminino , Genótipo , Frequência Cardíaca/fisiologia , Hipertensão/complicações , Hipertensão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/fisiopatologia , Fatores Sexuais
17.
Hypertension ; 76(2): 366-372, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32564693

RESUMO

Several factors have been proposed to explain the high death rate of the coronavirus disease 2019 (COVID-19) outbreak, including hypertension and hypertension-related treatment with Renin Angiotensin System inhibitors. Also, age and multimorbidity might be confounders. No sufficient data are available to demonstrate their independent role. We designed a cross-sectional, observational, multicenter, nationwide survey in Italy to verify whether renin-angiotensin system inhibitors are related to COVID-19 severe outcomes. We analyzed information from Italian patients diagnosed with COVID-19, admitted in 26 hospitals. One thousand five hundred ninety-one charts (male, 64.1%; 66±0.4 years) were recorded. At least 1 preexisting condition was observed in 73.4% of patients, with hypertension being the most represented (54.9%). One hundred eighty-eight deaths were recorded (11.8%; mean age, 79.6±0.9 years). In nonsurvivors, older age, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, coronary artery diseases, and heart failure were more represented than in survivors. The Charlson Comorbidity Index was significantly higher in nonsurvivors compared with survivors (4.3±0.15 versus 2.6±0.05; P<0.001). ACE (angiotensin-converting enzyme) inhibitors, diuretics, and ß-blockers were more frequently used in nonsurvivors than in survivors. After correction by multivariate analysis, only age (P=0.0001), diabetes mellitus (P=0.004), chronic obstructive pulmonary disease (P=0.011), and chronic kidney disease (P=0.004) but not hypertension predicted mortality. Charlson Comorbidity Index, which cumulates age and comorbidities, predicts mortality with an exponential increase in the odds ratio by each point of score. In the COVID-19 outbreak, mortality is predicted by age and the presence of comorbidities. Our data do not support a significant interference of hypertension and antihypertensive therapy on COVID-19 lethality. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT04331574.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Hipertensão/tratamento farmacológico , Pneumonia Viral/epidemiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sociedades Médicas , Adolescente , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/metabolismo , Estudos Transversais , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/metabolismo , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Multimorbidade/tendências , Pandemias , Pneumonia Viral/metabolismo , Prognóstico , Taxa de Sobrevida/tendências , Adulto Jovem
18.
Life Sci ; 256: 117915, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504752

RESUMO

AIMS: Autonomic dysfunction in arterial hypertension affects cardiorespiratory control and gastric motility and has been characterized by increased sympathetic and reduced parasympathetic activity. In the present work we investigated the effects of anticholinesterase drugs [donepezil (DON) or pyridostigmine (PYR)] on cardiovascular, autonomic, and gastric parameters in L-NAME-induced hypertensive rats. MATERIALS AND METHODS: Daily oral gavage of L-NAME (70 mg/kg/day) was performed over 14 days in male Wistar rats (180-220 g), whereas daily oral gavage of DON or PYR (1.6 and 22 mg/kg/day, respectively) started 2 days after the L-NAME treatment initiation and lasted 12 days. The development of hypertension was verified by tail plethysmography technique. After the end of treatments, the animals were subjected to experimental protocols (6-12 animals per group; total number of animals used: 78). KEY FINDINGS: L-NAME hypertensive animals had no alterations in heart rate (HR) and intrinsic HR, but showed reduction in baroreflex sensitivity, parasympathetic tone, and gastric motility; and the sympathetic tone, chemoreflex sensitivity, and the LF (low frequency) band of systolic arterial pressure (SAP) variability were increased. DON or PYR attenuated the increase in mean arterial pressure (MAP) induced by L-NAME. Both anticholinesterase drugs were effective in preventing the decrease in baroreflex sensitivity, parasympathetic tone and gastric motility, and also prevented the increases in peripheral chemoreflex response and cardiac sympathetic tone. SIGNIFICANCE: Acetylcholinesterase inhibition with DON or PYR is a promising pharmacological approach to increase parasympathetic function, thus preventing the hypertension-induced alterations in the cardiovascular, gastrointestinal and autonomic systems.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Hipertensão/prevenção & controle , NG-Nitroarginina Metil Éster/efeitos adversos , Substâncias Protetoras/farmacologia , Brometo de Piridostigmina/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Modelos Animais de Doenças , Donepezila/metabolismo , Donepezila/farmacologia , Frequência Cardíaca , Hipertensão/metabolismo , Masculino , Substâncias Protetoras/metabolismo , Brometo de Piridostigmina/metabolismo , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Volume Sistólico
19.
Hypertension ; 76(1): 16-22, 2020 07.
Artigo em Inglês | MEDLINE | ID: covidwho-611756

RESUMO

Potential but unconfirmed risk factors for coronavirus disease 2019 (COVID-19) in adults and children may include hypertension, cardiovascular disease, and chronic kidney disease, as well as the medications commonly prescribed for these conditions, ACE (angiotensin-converting enzyme) inhibitors, and Ang II (angiotensin II) receptor blockers. Coronavirus binding to ACE2 (angiotensin-converting enzyme 2), a crucial component of the renin-angiotensin-aldosterone system, underlies much of this concern. Children are uniquely impacted by the coronavirus, but the reasons are unclear. This review will highlight the relationship of COVID-19 with hypertension, use of ACE inhibitors and Ang II receptor blockers, and lifetime risk of cardiovascular disease from the pediatric perspective. We briefly summarize the renin-angiotensin-aldosterone system and comprehensively review the literature pertaining to the ACE 2/Ang-(1-7) pathway in children and the clinical evidence for how ACE inhibitors and Ang II receptor blockers affect this important pathway. Given the importance of the ACE 2/Ang-(1-7) pathway and the potential differences between adults and children, it is crucial that children are included in coronavirus-related research, as this may shed light on potential mechanisms for why children are at decreased risk of severe COVID-19.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus/fisiologia , Infecções por Coronavirus , Hipertensão , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral , Criança , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia
20.
Hypertension ; 76(1): 16-22, 2020 07.
Artigo em Inglês | MEDLINE | ID: covidwho-175967

RESUMO

Potential but unconfirmed risk factors for coronavirus disease 2019 (COVID-19) in adults and children may include hypertension, cardiovascular disease, and chronic kidney disease, as well as the medications commonly prescribed for these conditions, ACE (angiotensin-converting enzyme) inhibitors, and Ang II (angiotensin II) receptor blockers. Coronavirus binding to ACE2 (angiotensin-converting enzyme 2), a crucial component of the renin-angiotensin-aldosterone system, underlies much of this concern. Children are uniquely impacted by the coronavirus, but the reasons are unclear. This review will highlight the relationship of COVID-19 with hypertension, use of ACE inhibitors and Ang II receptor blockers, and lifetime risk of cardiovascular disease from the pediatric perspective. We briefly summarize the renin-angiotensin-aldosterone system and comprehensively review the literature pertaining to the ACE 2/Ang-(1-7) pathway in children and the clinical evidence for how ACE inhibitors and Ang II receptor blockers affect this important pathway. Given the importance of the ACE 2/Ang-(1-7) pathway and the potential differences between adults and children, it is crucial that children are included in coronavirus-related research, as this may shed light on potential mechanisms for why children are at decreased risk of severe COVID-19.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Betacoronavirus/fisiologia , Infecções por Coronavirus , Hipertensão , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral , Criança , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/metabolismo , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia
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